The global objective of this Mentored Patient-Oriented Research Career Development Award is to promote the candidate's career as an academic physician-scientist and to facilitate her transition to an independent investigator. To accomplish this goal, the candidate and her mentors have developed an integrated plan that combines an innovative idea of great clinical significance, cutting-edge science and advanced training in the techniques of patient-oriented research. LIT Southwestern provides a great infrastructure and an excellent academic environment to support the career development of young clinical investigators. This award will provide the candidate with the time, resources, and skills necessary for clinical and translational research in the field of diabetes. The proposed research plan will test if the lipotoxicity mechanism is a significant contributor to beta-cell dysfunction in humans. It is hypothesized that pancreatic triglyceride (fat) accumulation contributes to betacell failure and the development of type 2 diabetes. The relationship between ectopic fat acumulation in the pancreas and beta-cell function will be determined in Aim 1. In Aim 2 subjects planning to undergo bariatric surgery will be evaluated and followed for 1 year after the procedure. Changes in pancreatic fat content, beta-cell function, and insulin resistance will be described. The third Aim will assess if a drug intervention (pioglitazone) will reduce fat accumulation in the pancreas alongside with improvement of beta-cell function. A novel non-invasive magnetic resonance spectroscopy technique will be used to accurately and reliably quantify pancreatic fat content. Improved understanding of the pathophysiology of type 2 diabetes will aid the development of effective agents for diabetes prevention and even cure. Since type 2 diabetes has become so prevalent and is associated with high morbidity and mortality, such work has significant public health impact. Also, if pancreatic fat quantification proves to be a good predictor of beta-cell function, this novel non-invasive test could develop into a valuable clinical tool used to accurately predict the development of diabetes in high-risk subjects. The combination of advanced training in patient-oriented research and in-depth study of an important clinical problem will prepare the candidate for a Iong-term career as an independent investigator.